Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy.

Journal Article (Review)

Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Although only a few drugs have received regulatory approval for narcolepsy to date, treatment involves diverse medications that affect multiple biochemical targets and neural circuits. Clinical trials have demonstrated efficacy for the following classes of drugs as narcolepsy treatments: alerting medications (amphetamine, methylphenidate, modafinil/armodafinil, solriamfetol [JZP-110]), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), sodium oxybate, and the H3 -receptor inverse agonist/antagonist pitolisant. Enhanced catecholamine availability and regulation of locus coeruleus (LC) norepinephrine (NE) neuron activity is likely central to the therapeutic activity of most of these compounds. LC NE neurons are integral to sleep/wake regulation and muscle tone; reduced excitatory input to the LC due to compromise of Hcrt/orexin neurons (likely due to autoimmune factors) results in LC NE dysregulation and contributes to narcolepsy/cataplexy symptoms. Agents that increase catecholamines and/or LC activity may mitigate EDS and cataplexy by elevating NE regulation of GABAergic inputs from the amygdala. Consequently, novel medications and treatment strategies aimed at preserving and/or modulating Hcrt/orexin-LC circuit integrity are warranted in narcolepsy/cataplexy.

Full Text

Cited Authors

  • Szabo, ST; Thorpy, MJ; Mayer, G; Peever, JH; Kilduff, TS

Published Date

  • February 2019

Published In

Volume / Issue

  • 43 /

Start / End Page

  • 23 - 36

PubMed ID

  • 30503715

Pubmed Central ID

  • 30503715

Electronic International Standard Serial Number (EISSN)

  • 1532-2955

International Standard Serial Number (ISSN)

  • 1087-0792

Digital Object Identifier (DOI)

  • 10.1016/j.smrv.2018.09.006


  • eng